This document discusses epigenetic therapies for cancer treatment. It introduces DNA methylation and histone modifications as two main types of epigenetic modifications. It then reviews four FDA-approved epigenetic drugs - azacytidine, decitabine, vorinostat, and romidepsin - and their efficacy in treating various cancers like myelodysplastic syndromes and cutaneous T-cell lymphoma. The document finds that combination epigenetic therapies may have synergistic effects in solid tumors and help reduce side effects. Overall, the future of epigenetic cancer treatment likely involves effective combination approaches and more targeted epigenetic inhibitors.

1. EPIGENETIC THERAPY
AS CANCER TREATMENT
Janelle Leggere

2. Introduction: Epigentic modification
 Central dogma of molecular biology:
 DNA RNA Translation
Transcription
Protein
 Epigenetic modifications – molecular changes to the
structure of the genome that affect gene expression
with out altering the DNA.
 Two main types:
1. DNA Methylation
2. Histone Tail Modifications

3. Introduction: DNA Methylation
•CH3 inhibits transcription factors from attaching to DNA
•Gene(s) silenced/inactivated, esp. if promoter region is methylated
•Hypermethylation -> inactivated genes;
•Hypomethylation -> genomic instability
•Catalyzed by presence of DNA Methyltransferase (DNMT) enzymes

4. Introduction: Histone Tail Modifications
 Histone – basic protein around which a DNA
strand is wound to form chromatin
 Molecular modifications to the histone “tail”
(sticks out from the chromatin) determine how
tightly the DNA is wound
 Tightly wound DNA ->genes inactivated,
silenced
 Loosely wound DNA -> genes activated,
expressed

5. Introduction: Histone
Acetlyation/Deacetylation
•Acetylation: Addition of COCH3 groups;
•DNA more loosely wound -> genes expressed
•Deacetylation: Removal of COCH3 groups ;
•DNA more tightly wound -> genes silenced
•Deacetylation catalyzed by presence of Histone Deacetylase (HDAC)
enzymes

6. Introduction: Overview of DNA
Methylation and Histone Tail Modifcation
•Genes silenced if DNA is methylated
•Genes expressed if histone is acetylated

7. Genetic/Epigenetic Basis of
Cancer
 Cancer – unregulated growth of abnormal
cells; abnormal cell cycle
 Often caused by inactivation of tumor
suppressing gene
 Inactivation caused by loss of function mutation in
DNA
 OR caused by epigenetic gene silencing
 *genetic changes are irreversible, but
epigenetic changes are not!*

8. Current Cancer treatments
 Supportive treatment – care, not cure
 Radiation therapy – non- selectively
damages DNA of cells near tumor
 Fatigue, skin irritation
 Tumor removal surgery – often not plausable
 Traditional chemotherapy – non - selectively
targets all rapidly dividing cells
 nausea, loss of appetite, hair loss, brittle skin and
nails, fatigue, ect.

9. Epigenetic Cancer Treatments
 Attempt to inhibit and reverse the epigenetic
modifications that cause cancer
 Reactivate tumor suppressor genes
 Apoptotic genes, cell cycle regulators
 Inhibit the enzymes that catalyze epigenetic
modifications
 HDACs, DNMTs
 Currently 4 FDA approved epigenetic treatments for
cancer
 Treatments for cancers of the blood, bone marrow,
and lymph nodes
 Hematologic malignancies

10. DNMT Inhibitor Treatments
1. Azacytidine: “Vidaza” Subcutaneous
2. Decitabine: “Dacogen” IV
 Both used to treat Myelodysplastic
Syndromes (MDS)
 Bone marrow cancers; “prelukemia” -> 1/3
transform to Acute Myelgenous Leukemia (AML)
 Only used when conventional treatments
have failed
 Supportive care, stem cell transplant,
chemotherapy

11. Efficacy of Azacytidine and Decitabine
 In comparison to supportive care, both
hypomethylating agents:
 Had significantly higher rates of response, partial
response, improvement, and remission
 Had higher survival rate
 Delayed transformation to ALS
 Delayed death
 Increased overall wellbeing

12. Efficacy of Azacytidine and Decitibine
 Azacytidine
 60% response
 7% complete remission
 16% partial response
 37% improved
 2 yr survival rate twice that of conventional treatments
 Decitibine
 17-49% response
 Large variance
 Effect on chronic myelomoncyctic leukemia:
 25% response
 14% complete remission
 11% partial response
 11% improved
 39% stable disease

13. Draw Backs of Azacytidine and Decitabine
 Abnormal methylation patterns can return
 Side effects:
 Nausea, vommiting, anorexia, myelosuppression
(decrease in blood cell production)
 Thrombocytopenia – low platelet count
 Neutropenia – low white blood cell count
 Thrombocytopenia and neutropenia caused by
cytotoxicity of specific mechanisms which are
not related to the hypomethylating effect

14. HDAC Inhibitor Treatments
1. Vorinostat: “Zolinza,” pill form
2. Romidepsin: “Istodax,” IV
 Both treat cutaneous T-cell lymphoma
(CTCL)
 Cancers of the immune system; non-Hodgkin’s
lymphoma
 Both prove effective, with response rate
around 30%
 Both only prescribed when convetional
treatments have failed (Refractory CTCL)

15. Efficacy of Vorinostat and Romidepsin for
CTCL Treatment
 Vorinostat
 29.7% response
 Continued treatment 2yrs: (small n)
 16.7% complete remission
 66.7% partial remission
 16.7% stable disease
 Romidepsin
 34-35% response

16. Draw backs of Vorinostat and
Romidepsin
 side effects:
 Romidepsin
 86% nausea
 77% fatigue
 52% vomiting
 54% anorexia
 *cardiotoxicity
 Vorinostat
 26% thrombocytopenia
 14% anemia
 54% fatigue
 61% nausea
 31% Diarrhea

17. Efficacy of Single Epigenetic
Therapy on Solid Tumor cancers
 Azacytidine – no effect published
 Decitadine – no effect published
 Vorinostat – small effect on:
 Colorectal, breast, head and neck, and prostate
cancer
 Small sample size, small effect size (5-8%)
 Very severe side effects; some results were
jeopardized
 Romidepsin – shown small effect on:
 refactory AML/MDS, CLL, lung cancer, hormone
refractory cancer
 Small sample sizes, small effect size (4-9%)

18. Efficacy of Combined Therapies on
Solid Tumor cancers
 Addition of Azacytidine to conventional
chemotherapeutic agents(docetaxel & cisplatin)
increased response of refractive prostate cancer 13%
 Addition of Vorinostat to conventional
chemotherapeutic agents (carboplatin & paditaxel)
increased response rate of non-small cell lung
carcinoma 22%
 Combination of Decitabine and two HDAC inhibitors
(LBH589 or MGCD0103) had synergistic effect on
small cell lung cancer cells; reduced proliferation of
56% or strains
 Addition of Decitabine to radiation therapy of breast
cancer cells increased response rate 33%

19. Future Potential Of Combination
Therapy
 Apparent synergistic effects of epigenetic
therapies
 Epigenetic therapy is not a cure; combination
with chemotherapy/radiation could be
 Negative side effects were muted when paired
with other chemotherapeutic drugs
 Esp. Vorinostat

20. Conclusions
 Epigenetic therapies improvement on past
treatments, especially when combination
approach
 Seems future is in finding effective
combinations
 Also, efforts should be made to make the
inhibitors more selective in order to lessen the
side effects